rs12102203

Positions:

• chr15-51499362-A-C
• chr15-51499362-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001378457.1(DMXL2):​c.3862T>G​(p.Ser1288Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1288P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: DMXL2 NM_001378457.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269

Genes affected

DMXL2 (HGNC:2938): (Dmx like 2) This gene encodes a protein with 12 WD domains. Proteins with WD domains are involved in many functions including participation in signal transduction pathways. Participation of the encoded protein in regulation of the Notch signaling pathway has been demonstrated in vitro using several human cell lines (PMID:20810660). A gene encoding a similar protein is located on chromosome 5. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DMXL2. . Gene score misZ 2.3662 (greater than the threshold 3.09). Trascript score misZ 3.2988 (greater than threshold 3.09). GenCC has associacion of gene with polyendocrine-polyneuropathy syndrome, autosomal dominant nonsyndromic hearing loss, nonsyndromic genetic hearing loss, hearing loss, autosomal dominant 71, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 81.
• BP4: Computational evidence support a benign effect (MetaRNN=0.067620575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMXL2	NM_001378457.1	c.3862T>G	p.Ser1288Ala	missense_variant	18/44	ENST00000560891.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMXL2	ENST00000560891.6	c.3862T>G	p.Ser1288Ala	missense_variant	18/44	1	NM_001378457.1	A1
DMXL2	ENST00000543779.6	c.3862T>G	p.Ser1288Ala	missense_variant	18/43	1		P4
DMXL2	ENST00000251076.9	c.3862T>G	p.Ser1288Ala	missense_variant	18/43	1		A1
DMXL2	ENST00000449909.7	c.2765-4228T>G		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250686 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461596 Hom.: 0 Cov.: 55 AF XY: 0.00000550 AC XY: 4 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.66
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.12	T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.021
Sift	Benign	0.57	T;T
Polyphen		0.0010	B;.
Vest4		0.036
MutPred		0.15		Loss of glycosylation at S1288 (P = 0.0354);Loss of glycosylation at S1288 (P = 0.0354);
MVP		0.20
MPC		0.17
ClinPred		0.022	T
GERP RS		1.7
Varity_R		0.044
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12102203; hg19: chr15-51791559;